Project 3 An injury to the nervous system induces chronic changes in synaptic activity. Experimentally produced changes in synaptic activity have been shown to induce compensatory changes in synaptic strength. This modulation has been termed homeostatic since the changes are in the direction that maintains network activity at its normal level. Most studies of homeostatic modulation have used manipulations that up- or down-regulate presynaptic and postsynaptic activity in parallel. After an injury the situation is likely to be more complex. Partial denervation of a cell may reduce postsynaptic activity but have little, or no, effect on the level of activity of its remaining inputs. The result will be chronic mismatches in pre-and postsynaptic activity. In this situation it is unclear what the "homeostatic response" would be. In the most popular version of the homeostatic hypothesis the postsynaptic cell is the key element. The postsynaptic cell is proposed to sense a change in its activity and react by increasing its own responsiveness to all its inputs. However, recent results in the literature, and our own studies, suggest a different view. We believe that both thepre- and the postsynaptic elements are important in the response to a chronic change in activity. In our model, changes in activity of the presynaptic and postsynaptic cells trigger distinct sets of changes in synaptic properties. Our model can better account for previously published findings following chronic mismatches of pre- and postsynaptic activity than can the current homeostatic model. In this proposal, we will use the mammalian neuromuscular junction and will independently alter pre-and postsynaptic activity to determine which model can better predict changes in synaptic strength triggered by altered activity. Understanding injury-induced plasticity of synaptic strength is an essential step in the search for therapeutic strategies. Only when we understand how the nervous system responds to injury will we be able to harness these mechanisms to promote more extensive recovery.